Chediak-Higashi syndrome (CHS) is a lethal autosomal recessive disorder of humans mapping to 1q43. The clinical manifestations of this disorder include hypopigmentation, defective immune cell function, including severely impaired natural killer cell activity, and defective antibody-dependent, lymphocyte-mediated cytolysis against tumor cell targets. Further, neural degeneration is observed and, finally, the occurrence of a mononuclear cell lymphoma develops, which causes the death of afflicted individuals.
As mentioned above, the disease is accompanied by a marked susceptibility to infections. Young children have repeated infections, usually with gram-positive organisms of the staphylococcal and streptococcal type. Further, during the course of the disease, children may develop a progressive peripheral neuropathy. Children surviving the early infectious episodes (8-18 years of age), most frequently develop terminal lymphoreticular malignancy. Few patients survive beyond twenty years.
Pathological manifestation of the syndrome includes enlarged vesicles affecting lysosomes, melanosomes, platelet dense granules, cytolytic granules and Schwann cell granules. The abnormal size of these vesicles is thought to result from a malregulation of vesicle fusion or fission. Abnormal membrane-bound lysosomal-like organelles have been found in cells of the buccal mucosa, Schwann cells, pancreas, liver, gastric and duodenal mucosa, adrenal, pituitary, spleen, kidney, bone marrow, hair skin, iris and conjunctiva. The giant granules observed resemble the normal granules of the specific cell type in both fine structure and cytochemic reactions and result from the fusion of small primary granules.
Similar phenotypes are found in other species, most notably the beige mouse and the Aleutian mink, but are also found in such species as the Persian cat, cattle and even the killer whale. Somatic cell fusion studies have suggested that mutations within the same gene in mouse, mink, and man were responsible for the CHS-like phenotype in each of these species. In mice, the gene responsible for such a phenotype is the beige (bg) gene. Such studies, however, were not able to elucidate either the function or the identity of the bg gene product.
Over the past thirty years numerous theories have been evoked to explain the nature of these disorders. For example, it has been suggested that the defect might be caused by alterations in membrane fluidity, defects in microtubules or microtubule associated proteins, or changes in cyclic nucleotides levels. Upon further examination, though, each of these theories has been found to be inadequate, thus highlighting the fact that a great need remains for the discovery of the causative agent of the lethal Chediak-Higashi syndrome genetic disorder.